Project Summary/Abstract PediAtric ReseArch of Drugs, Immunoparalysis and Genetics during MODS (PARADIGM) Failure of the immune system is common in the setting of pediatric multiple organ dysfunction syndrome (MODS) and is associated with high risks for secondary infection, persistent organ failure, and death. When severe, this is termed ?immunoparalysis.? This form of immune system failure can be defined as reduced ability of whole blood to produce the cytokine tumor necrosis factor (TNF)-? upon ex vivo stimulation with lipopolysaccharide. We have developed a highly standardized, small-volume, easy-to-process approach to this testing that is used in multi-center studies of immune function. Our group has studied immunoparalysis for nearly two decades in children from varying diagnostic groups including sepsis, trauma, cardiopulmonary bypass, and viral infections, but these studies have been limited by small sample sizes. Although our testing approach has identified thresholds of innate immune function that strongly predict adverse outcomes from pediatric critical illness, these thresholds may vary by diagnostic group and have not been validated in a large independent cohort. It is well known that certain conditions and treatments overtly result in impaired immune function (e.g. malignancy), but the implications of most acute and chronic diagnoses on immune function remain unclear. In addition, many commonly used drugs in the pediatric intensive care unit (PICU) (e.g. hydrocortisone, sedatives, analgesics) have unintended immune effects, though their magnitude is unclear. Lastly, the influence of the host genome on immune function in this setting is unknown. Clinical trials are ongoing in critically ill adults and children targeting the reversal of immunoparalysis, but there are currently no studies targeting the prevention of immunoparalysis, largely due to a lack of understanding of risk factors. The overall goal of our research program is to reduce the incidence of immunoparalysis and its associated risks for infection, organ failure, and death. The PARADIGM study is a 1400-subject, multi-center, prospective, observational study to test the central hypothesis that the risk for development of immunoparalysis in children with MODS can be predicted from diagnosis-specific, treatment-specific, and host-specific factors. Goals to be achieved for the first time as a result of the PARADIGM study include: confirmation, in a very large cohort of children with MODS, of thresholds of TNF? production capacity that are associated with death, prolonged organ dysfunction, and nosocomial infection; identification of diagnoses and ICU therapies that predispose children to, or prolong, immunoparalysis; and identification of candidate host genomic factors that may predispose children to, or prolong, immunoparalysis independent of diagnostic or treatment factors. This work will advance the field through 1) improved design of targeted clinical trials of immune stimulation; 2) avoidance of treatment regimens that predispose children with MODS to immunoparalysis; 3) development and testing of precision-medicine approaches to immune care in the PICU; 4) collection of a critical mass of data on the TNF? response sufficient to move the assay from the research environment to the clinical laboratory.